Article pubs.acs.org/crystal
Impurity Effect of L‑Valine on L‑Alanine Crystal Growth Xiangyu Yang, Gang Qian, Xuezhi Duan, and Xinggui Zhou* State Key Laboratory of Chemical Engineering, East China University of Science and Technology, Shanghai, 200237, China ABSTRACT: The effect of L-valine on the growth of the Lalanine (011) surface from solution crystallization is studied by combining single-crystal growth experiments and molecular simulation. For the first time, an unusual promotion effect of Lvaline on L-alanine crystal growth, after the initial inhibition effect, is found when the impurity concentration is higher. Through molecular simulation, it is revealed that this unusual promotion effect is due to the close interaction between Lalanine and L-valine, which repels H2O around solute molecules and therefore eliminates the negative effect of H2O on surface diffusion of L-alanine.
1. INTRODUCTION In solution crystallization, crystal growth, which proceeds by sequential addition of solute to bulk crystal, is greatly influenced by the presence of impurities and their concentrations.1,2 It is well-known that, in most cases, impurities will inhibit crystal growth,3−7 but in some cases, they can also promote crystal growth.8−10 The classical Cabrera−Vermilyea (C-V) theory,3 which accounts for the growth inhibition by the impurities’ pinning of elementary steps, has been widely adopted to interpret the inhibition effects of impurities and is validated by both experiments11−18 and simulation.19−24 The retarding effect is also attributed to the competitive adsorption and surface migration between solute and impurity molecules. However, the promotion effects of impurities are not comprehensively understood so far. As an example, for Lisoleucine crystal growth in the presence of impurity L-leucine, Anuar et al. showed that the calculated slice energy of the impurity-substituted (100) surface was more negative than that of the pure surface, an indication of easy binding of the impurity on this surface,8 whereas in experiments, the growth rate of the (100) surface was shown to increase in the presence of L-leucine. This result neither follows the C-V theory nor can be explained by the competitive adsorption and migration. Sangwal assumed that the three-dimensional impurity clusters on the surface might serve as additional sources of growth steps and hence promote crystal growth.9 Using this model, he was able to explain the promotion effects of Co2+ ions on the crystal growth of the NaNO3 (101̅1) surface and Cr3+ and Fe3+ ions on the crystal growth along the ⟨001⟩ direction of KDP.25 However, this model is valid only when insoluble impurities precipitate on crystal surfaces as clusters. To the best of our knowledge, the mechanism of growth promotion induced by mobile impurities is still unrevealed, and a generally accepted atomistic level description has not yet been reported in the literature. An in-depth understanding of the impurity-mediated crystal growth calls for a detained kinetic © 2013 American Chemical Society
analysis of the surface phenomena. However, because of the complexity of crystal interfaces and the limitation of detection techniques, the kinetics of crystal growth is hard to access by experimental methods. On the contrary, the molecular dynamics (MD) technique appears to be a promising way to probe the kinetic process of crystal growth when impure molecules are present in the solution. In this work, solution crystallization of L-alanine is studied by combining single-crystal growth experiments and molecular simulation, where L-valine is chosen as the impurity because the two molecules have very similar structures. It is shown by experiments that the crystal growth is retarded at a lower impurity concentration, but is promoted at a higher impurity concentration. These phenomena are rationally explained by MD simulation of solute adsorption on relaxed interfaces in the presence of L-valine. Both nonsolvated and solvated crystal interfaces are considered, and the critical importance of surface diffusion is validated when predicting the impurity effect on crystal growth.
2. METHODS 2.1. Experiments. Guaranteed reagents L-alanine and L-valine (>99%) were purchased from Adamas, and ultrapure water (ELGA PURELAB Classic, 18.2 MΩ·cm) was used in all the experiments. To grow high-quality single crystals of L-alanine, the crystallizing solutions in all experiments were filtered through a 0.22 μm membrane. First, single L-alanine crystals were grown by slow evaporation of solvent.26 Specifically, L-alanine, with an amount equivalent to its solubility of 25 °C, was completely dissolved into water at a higher temperature of 35 °C. The hot solution was filtered and slowly cooled to and maintained at the saturated temperature of 25 °C, during which the vial was covered by filter papers to ensure that the evaporation rate of solvent was slow enough for growing single crystals. Several days later, wellReceived: November 30, 2012 Revised: January 12, 2013 Published: January 18, 2013 1295
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formed single crystals of L-alanine with a length of 3−4 mm along the c axis and 2−3 mm along the b axis were obtained. The Miller indices of the crystal surfaces of L-alanine were determined by measuring the interfacial angles using an optical microscope (ECLIPSE E200, Nikon, Japan). Single-crystal growth experiments were then performed to measure the growth rates of L-alanine in the presence of L-valine under stagnant condition. The impurity concentration used in this study ranged from 0 to 1.0 wt %, and the solution supersaturation was kept at a constant value of σ = 0.01, low enough to avoid spontaneous nucleation during crystal growth (σ = (C − Ceq)/Ceq, where C is the actual solution concentration and Ceq is the solution concentration at equilibrium). The supersaturated impure solutions were prepared by dissolving appropriate amounts of L-alanine and L-valine into water at 35 °C, and then the solutions were filtered and slowly cooled to 25 °C. The asobtained single crystals of L-alanine were quickly washed with pure saturated solution and pure water to reduce the crystal imperfection as much as possible. High-quality crystals, selected via an optical microscope, were placed into the crystallizing solutions and allowed to grow for 7 days, during which the vials were sealed to prevent solvent evaporation. The amount of crystallizing solution was large enough to ensure that the supersaturation change (Δσ ≤ 0.0015) could be neglected. The growth rate of the (011) surface was obtained by measuring crystal sizes before and after the crystal growth. All experiments were duplicated to check the reproducibility. 2.2. Simulation. MD simulations with the canonical ensemble (NVT, constant particle number, volume, and temperature) were performed by employing Materials Studio 5.0 (Accelrys Software Inc.: San Diego, CA, 2009) to study the solute and impurity adsorption on nonsolvated and solvated crystal interfaces, during which the longrange interactions were calculated using the Ewald summation method. To find a proper forcefield with atomic charge distribution that can reproduce the experimental structure of L-alanine crystal, the unit cell adopted from the Cambridge Structural Database (CSD), with four molecules crystallizing into the orthorhombic space group P212121,27 was optimized using alternative forcefields of CVFF (Consistent Valence Force Field), PCFF (Polymer Consistent Force Field), COMPASS (Condensed-phase Optimized Molecular Potentials for Atomistic Simulation Study), and UNIVERSAL with the forcefield assigned charges and the equilibration and Gasteiger charge rules. With the CVFF and the forcefield assigned charges, the crystal structures before and after optimization had close similarities, and the calculated lattice energy (−70 kcal·mol−1) was very close to the experimental lattice energy derived from experimental sublimation enthalpy (Elatt = −ΔHsub − 2RT + Erel = −66 kcal·mol−1, where ΔHsub is the experimental sublimation enthalpy and Erel is the relaxation energy).27,28 Therefore, the CVFF forcefield with the forcefield assigned charges was used in all the following simulations. On the basis of the optimized unit cell, the surface of L-alanine was cleaved, extended, and rebuilt into a three-dimensional periodical box. The surface dimensions were larger than 30 Å, and the thickness of the vacuum was 50 Å to make sure that the nonbonded interactions can reach their asymptotic values. The stepped crystal interface was then built according to the strength of the hydrogen bonds of molecules in the crystal. The linkage of molecules in the crystal was maintained by the strong hydrogen bonds, and hence the step was built along the weakest hydrogen bonds chain. The molecules in the top layer of the stepped interface were relaxed first. The solvated interface was obtained by putting a preminimized solvent layer upon the interface for dynamics equilibrium. The growth behavior of L-alanine in the presence of L-valine was studied on both solvated and nonsolvated interfaces, where solute and impurity molecules were randomly docked on the surfaces. The total number of solute and impurity molecules on the built stepped interface was calculated to be eight, and the number ratios of L-valine/L-alanine studied here were 0/8, 1/7, and 4/4 to account for the concentration effect of the impurity. All the simulation boxes were dynamically calculated for at least 200 ps with a time step of 1 fs to reach equilibrium, and the average simulation results were obtained within the following 200 ps.
3. RESULTS AND DISCUSSION 3.1. Effects of L-Valine on Crystal Growth of L-Alanine. It can be seen in the inset of Figure 1 that the crystal habit of L-
Figure 1. Relative growth rates of the (011) surface of L-alanine in the presence of L-valine at σ = 0.01. The inset shows the crystal habit of Lalanine grown from pure aqueous solution.
alanine grown from pure aqueous solution is elongated along the crystallographic c axis, as depicted in the studies on the growth and characterization of L-alanine single crystals.26,27,29 The single-crystal growth experiments from impure aqueous solution show that the growth rate of the L-alanine (011) surface is significantly influenced by the presence of L-valine. In the low impurity concentration region, the rate of crystal growth is slowed, and the larger the impurity concentration, the more significant the inhibition effect. This is similar to the impurity effects of L-leucine and L-phenylalanine on L-alanine crystal growth reported in the literature.30,31 However, in the high impurity concentration region, with the increase of the Lvaline concentration, the growth of the (011) surface of Lalanine is surprisingly promoted. The crystals become much longer along the c axis. The growth inhibition at lower L-valine concentrations is closely related to impurity adsorption on the L-alanine crystal surface, as depicted in the C-V theory. Our previous study using MD simulation indicated that L-valine molecules on the (011) surface was mobile when considering the selectivity of impurity's adsorption on steps and terraces, and gave a rational explanation of the growth-inhibition phenomenon.32 However, at higher L-valine concentrations, the impurity promotes rather than inhibits the growth of the (011) surface, which violates the C-V theory. This indicates that, instead of pinning crystal steps, the mobile L-valine molecules tend to facilitate the diffusion and precipitation process of the solute. However, the mechanism, whether it is due to a kinetic promotion effect or a steric promotion effect,9 is not known from the experiments. Here, simulation of L-alanine solute adsorption on the (011) surface at the atomistic level is performed to resolve the problem. 3.2. Crystal Growth under Different Mechanisms of Impurity Effect. To verify whether the three-dimensional impurity clusters on the surface serve as additional sources of growth steps, two types of L-valine steps at the L-alanine (011) surface are classified, according to their precipitation sites at crystal terraces or crystal steps. The assumed impurity steps are considered to be a single impurity molecule of L-valine for simplicity. Solute adsorptions at the two types of impurity steps are investigated by MD simulation. Table 1 shows the average 1296
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Table 1. Average Adsorption Energies of Solute at Two Types of L-Valine Steps on the (011) Surface
Figure 2. Mean square displacement of L-alanine on the solvated crystal interface in the presence of L-valine with different L-valine/L-alanine ratios. The corresponding diffusivities are shown in the round brackets.
valine/L-alanine = 4/4). Thus, L-valine executes the impurity effects on L-alanine crystal growth by altering the diffusion kinetics of the solute on the crystal surface, and the solute diffusion is inhibited by lower impurity concentrations and promoted by higher impurity concentrations. The growth rate of the L-alanine (011) surface is, therefore, decreased in the presence of a small amount of L-valine, and then increased with a larger amount of L-valine, the same with the experiments. Whereas the L-valine in the nonsolvated simulation boxes for understanding the impurity step mechanism is confirmed to have little influence on L-alanine adsorption, the L-valine in the solvated simulation boxes is shown to largely influence the surface diffusion of L-alanine. Therefore, a detailed analysis focusing on solute adsorption under the influence of both solvent and impurity is performed based on the MD simulations. 3.3. Role of Solvent on Surface Adsorption. The adsorption conformations of L-alanine and L-valine on the nonsolvated and solvated interfaces have different hydrogen bonding schemes, as shown in Figure 3. Table 2 gives the angle and length distributions of the main hydrogen bonds between the adsorbate and the crystal interfacial molecules. On the nonsolvated interface, L-alanine forms hydrogen bonds with the interface molecules through both COO− and NH3+ mainly by O1 (L-alanine)···H1 (crystal) and N−H3 (L-alanine)···O1 (crystal), as circled in Figure 3a. O2 of L-alanine cannot form a hydrogen bond with the interface because of the coplanarity of the carboxyl group. The unstable hydrogen bonds of N−H1 (L-alanine)···O1 (crystal) and N−H1 (L-alanine)···O2 (crystal) are also observed. Thus, a parallel type adsorption of L-alanine on the nonsolvated interface is expected. When the surface is solvated, L-alanine interacts with the interface only by COO−
adsorption energies of solute at the two types of impurity steps (Eads L-valine(L-alanine)) and at the pure stepped crystal surface (Eads (L-alanine)) and the average adsorption energies of Lvaline at the stepped surface (EL‑valine). Obviously, for each case, the average adsorption energy of L-alanine at the assumed Lvaline step almost equals the sum of the adsorption energies when L-alanine and L-valine are separately adsorbed. This indicates that the nonbonded interactions between L-alanine and L-valine are neglectable, and the preadsorbed L-valine cannot provide a preferred adsorption site for L-alanine. Moreover, the simulation implies that the surface adsorption of L-alanine is not influenced by the presence of L-valine, and cannot account for the growth phenomenon in Figure 1. The impurity effect in this study is not due to the steric promotion effect. The solute diffusion is also estimated by MD simulation of the solvated surface with different ratios of L-alanine/L-valine (0/8, 1/7, and 4/4). The mean square displacement of Lalanine as a function of simulation time is plotted in Figure 2. It can be seen that the movement and surface adsorption of Lalanine are affected by L-valine and its concentrations, different from the results in Table 1. The corresponding diffusivities of Lalanine are derived using the following equation and are shown in the round brackets in Figure 2. D∞ =
1 d lim 6N∞ n →∞ dt
N∞
∑ ⟨[ri(t ) − ri(0)]2 ⟩ i=1
(1)
Clearly, compared with the diffusivity of L-alanine in pure solution (L-valine/L-alanine = 0/8), it becomes much smaller when the impurity concentration is low (L-valine/L-alanine = 1/ 7), and larger when the impurity concentration is high (L1297
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solute molecules tend to move across the crystal surface to enter into more stable sites. In solution, the presence of solvent complements the energy loss to a certain degree, resulting in more stable adsorption. Thus, the surface diffusion of solute is limited. Moreover, L-alanine is adjusted to be perpendicularly adsorbed on the surface by the H2O molecules around it, closely resembling the conformation of the crystalline molecules beneath. The similarity between them implies that the solvated solute is firmly balanced by forming hydrogen bonds with H2O, and its potential energy is much lower, like that of the molecules in the crystalline state. Therefore, the perpendicularly adsorbed L-alanine has a small diffusivity. Consequently, the growth of the (011) surface is greatly inhibited by the solvent owing to its negative effect on solute diffusion. As for L-valine, its adsorption conformations upon nonsolvated and solvated surface have little difference, and its surface diffusion is not influenced by H2O. In summary, the surface diffusion of solute is not influenced by impurity (see section 3.2) but is limited by solvent; understanding the mechanism of growth promotion by impurity should take into consideration the coeffects of solvent and impurity. 3.4. Simulation of Surface Diffusion-Promoted Crystal Growth. L-valine molecule is introduced into the equilibrium system of solvated interface and adsorbed L-alanine, and MD simulation is allowed for 400ps. Figure 4 exhibits the snapshots of the results as a function of simulation time. When the Lvaline is far from the L-alanine and H2O directly forms hydrogen bonds with the L-alanine, the L-alanine exhibits the perpendicular type of adsorption at the interface (Figure 4a). When the distance between the L-alanine and the L-valine decreases and no room is left between them to accommodate H2O molecules, the L-alanine changes into and remains as the parallel type of adsorption (Figure 4b). In this case, a hydrogen bond of N−H3 (L-alanine)···O2 (L-valine) is formed, as marked by the bold dashed line in Figure 4c, which is easy to break off at times, yielding two nearby, but separated, adsorbate molecules. From the corresponding average potential energy that changes little during the separation and rebinding, it is again concluded that the diffusion of the L-alanine and L-valine is not limited by the hydrogen interactions. Owing to the closeness between the L-alanine and the L-valine, the H2O around the L-alanine is repelled and its retarding effect on the surface diffusion of L-alanine is eliminated. In other words, LAlanine on solvated interface presents the same adsorption type on nonsolvated interface, and the diffusivity of solute is freed from the negative influence of solvent. This explains the unusual promotion effect of L-valine on the crystal growth of Lalanine. As revealed by the MD simulation, modification of surface diffusion is enabled only by the impurity molecules nearby the solute molecules, which implies that the distribution of
Figure 3. Adsorption structures of L-alanine (upper) and L-valine (lower) on the nonsolvated (a, c) and solvated (b, d) crystal interfaces (L-alanine: stick; L-valine: ball and stick. Crystal molecules: line; H2O: green line. The same legend is used in Figure 4).
(Figure 3b). The strong hydrogen bonds, i.e., O2 (Lalanine)···N−H1 (crystal), and O2 (L-alanine)···N−H3 (crystal), and the weak hydrogen bond, i.e., O1 (L-alanine)···N−H3 (crystal), as marked by circles, are noticed to be similar to those between the crystalline molecules. In addition, O1 and all three H of NH3+ strongly interact with H2O via three to four hydrogen bonds each. The solute molecule exhibits a perpendicular type adsorption, and the conformation and orientation of the solute closely resemble those of the crystalline molecules beneath. In contradistinction, the adsorption conformations of L-valine on nonsolvated and solvated interfaces are almost identical (Figure 3c,d). Both of them are bound by virtue of interactions between its similar part with L-alanine and the neighboring substrate molecules, in a very similar way to the solute molecules on the nonsolvated interface. The distinct influences of H2O on surface adsorption of Lalanine and L-valine imply that the adsorption stabilities and diffusivities of L-alanine and L-valine will be varied accordingly. In general, the diffusion of solute is retarded by the presence of foreign molecules at the crystal interface, and therefore the crystal growth is inhibited.33 As we know, different from molecules in bulk crystal, the top layer molecules, especially the solute molecules at the interface, suffer imbalanced forces because they are only constrained on one side. As a result,
Table 2. Strong Hydrogen Bonds between L-Alanine/L-Valine and Crystal Molecules (L-Alanine/L-Valine···Crystal) on the Nonsolvated and Solvated Interfaces nonsolvated
solvated
(011)
H-bond
length/Å
angle/deg
H-bond
length/Å
angle/deg
L-alanine
O1···H1 H3···O1 O1···H1 H1···O1 H3···O2
1.5−2.0 1.6−2.1 1.6−1.9 1.6−2.0 1.6−2.0
148−179 136−170 149−177 140−179 141−176
O2···H1 O2···H3 O1···H3 H1···O1 H3···O2
1.5−2.1 1.7−2.4 2.0−3.0 1.6−2.2 1.6−2.2
145−180 126−169 102−165 145−179 144−177
L-valine
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Figure 4. Snapshots of the L-alanine adsorption with the influence of nearby L-valine (the same legend as that in Figure 3).
importance of combining crystal growth experiments and the molecular simulation approach for understanding the effects of surface diffusion on crystal growth in the presence of impurities.
impurity molecules on the crystal surface is of primary importance for promoting crystal growth. Because of the mobile feature of L-valine on the crystal surface, the distribution is largely determined by its concentration. Using AFM, Nakada et al. also observed that the impurity molecule on the lysozyme (101) surface appeared to be randomly distributed; its density relied on its bulk concentration but did not change with time.34 In this study, L-valine with lower concentrations cannot perform the promotion effect on L-alanine crystal growth because of a large average distance between solute and impurity molecules, and the growth mechanism follows the classical C-V theory, as deduced in our previous study.32 When the impurity concentration is increased, L-valine and L-alanine molecules become close enough to repel the H2O molecules around Lalanine that retard the mobilities of L-alanine. Our simulation gives a qualitative estimation of the impurity effects. Simulating a real crystal growth process will be very expensive because of the complexity of the real crystal interface, especially when the relaxation of the crystal interface has to be considered. In this study, impurity concentrations used for experiments and simulations are different, and it is difficult to estimate the difference because only the molecular events at the interface are studied by MD simulation, whereas in the experiments, one can only adjust the averaged concentrations. Nevertheless, the MD simulation reveals the competitive inhibition of the crystal growth of solvent and impurity molecules. At larger impurity concentrations, some interfacial solvent molecules that exert a stronger inhibition are replaced by impurity molecules having less influence, thus relieving the inhibition by solvent molecules and promoting crystal growth. At lower impurity concentrations, the traditional C-V theory holds true. The combination of these two mechanisms, that is, the impurity’s pinning at the steps and the solute’s diffusion on the crystal surface, explains the experimental observations of the inhibited growth at lower impurity concentrations and the promoted growth at higher impurity concentrations.32
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AUTHOR INFORMATION
Corresponding Author
*Tel: +86-21-64253509. Fax: +86-21-64253528. E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work is financially supported by the 111 Project of the Ministry of Education of China (B08021).
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REFERENCES
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4. CONCLUSION An unusual promotion effect of L-valine on the growth of the Lalanine (011) surface from solution crystallization is observed by experiment and is rationally illuminated by the surface diffusion-promotion mechanism. Through MD simulation, it is qualitatively revealed that H2O molecules, which form hydrogen bonds with L-alanine, limit the mobility of L-alanine on the surface, thus inhibiting the surface growth. At high Lvaline concentrations, L-valine frees L-alanine from the confinement of H2O by approaching L-alanine molecules to repel H2O molecules around them, and eventually promotes the crystal growth. This study demonstrates the critical 1299
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